Symptomsofanxiety,avoidanceandarousal(?AAA?)cansignificantly,andnegatively,impactonone?sday- to-dayfunctioningandqualityoflife.Thisisespeciallytrueforgirlsandwomenwhoaremorethantwiceas likelytobediagnosedwithananxietydisorderwhencomparedtomen.Theproposedprojectaddressesthe pathogenesisofAAA,threeofthenegativevalanceRDoCsystems,inthecontextofaspecificgeneticriskfor suchsymptomsingirlswiththeFMR1fullmutation(i.e.fragileXsyndrome,FXS).Itisbroadlyrecognizedthat AAAsymptomsareanimportantandclinicallysignificantproblemforgirlsandwomenwithFXS.Recent surveyreportsindicatethat56%ofgirlswithFXShavereceivedtreatmentforananxietydisorder.Females withFXS,whoareunderrepresentedinresearchstudies,haveamorediverserangeofsymptomsandoverall higherIQthanmaleswithFXS,whichallowsfemalestoplayaparticularlyimportanttranslationalrolein understandingthecomplexitiesoftheAAAphenotype. UsingFXSasahumanmodelsystem,criticalgapsinourknowledgebaseregardingAAAsymptomswill beaddressed.Thisprojectwillemployanacceleratedlongitudinaldesigntotracksymptomdevelopmentin60 girlswithFXSfromages8-15years,andlinearmixedmodelingtoestimatechangeassociatedwithage.The developmentofnegativevalenceRDoCsystemswillbetrackedintandemwithkeyneuralsystemswhile consideringgenetic,hormonal,andenvironmentalfactorsthatmaycontributetotheclinicalpresentationof AAAsymptoms.Thismultimodalapproachwillfacilitatecomprehensiveanalysisofgene-brain-behavior interactionsthatunderlieAAAsymptoms.Ourdesignwillallowustotestnovelhypothesesregardingthe courseofAAAsymptomsandexaminemediatingfactorssuchasHPAaxisregulation.Combiningtraditional functionalandstructuralmetricsofbrainconnectivitywillallowusprobetheprefrontal-limbiccircuitryknownto haveakeyroleinAAAsymptoms.Utilizingflexible,opticalneuroimaging(functionalnearinfrared spectroscopy,fNIRS),wewillexamineprefrontalcorticalresponsestoanxietyduringnaturalisticsocial interactionstoyieldecologicallyvalidassessmentsofrealtimeanxietyresponseinvivo. Theprojectproposedherebuildsonsubstantialresearchinthepastgrantperiodfocusedongene- environment-brain-behaviorassociationsinfemaleswithFXS.ThecombinationofnewknowledgeaboutFXS thathasbecomeavailableinthepastseveralyearsandnewmethodsforinterrogatingtheseassociations providesanidealfoundationfromwhichnewhypothesescanbetestedinthenewgrantperiod.Plottingthe trajectoryofAAAsymptomdevelopmentandexaminingkeylinkageswithneurobiology,physiology,hormones, genesandenvironmentwilladvancethescientificknowledgebaseregardingthepathogenesisofAAAinFXS. Theseresultswilladvanceclinicalpracticebyidentifyingcriticalwindowswheninterventionsandpreventative strategieswillbemosteffectiveandhelptoadvanceaprecisionmedicineapproachwithinFXS. 1